Abstract

We previously demonstrated that IgG responses to a panel of 126 prostate tissue-associated antigens are common in patients with prostate cancer. In the current report we questioned whether changes in IgG responses to this panel might be used as a measure of immune response, and potentially antigen spread, following prostate cancer-directed immune-active therapies. Sera were obtained from prostate cancer patients prior to and three months following treatment with androgen deprivation therapy (n = 34), a poxviral vaccine (n = 31), and a DNA vaccine (n = 21). Changes in IgG responses to individual antigens were identified by phage immunoblot. Patterns of IgG recognition following three months of treatment were evaluated using a machine-learned Bayesian Belief Network (ML-BBN). We found that different antigens were recognized following androgen deprivation compared with vaccine therapies. While the number of clinical responders was low in the vaccine-treated populations, we demonstrate that ML-BBN can be used to develop potentially predictive models.

Schema for sample collection. Sera were collected from men with prostate cancer undergoing treatment on three separate clinical trials. Shown are the timing of blood collection and basic schema for these studies. In one study, blood was collected immediately preceding, and at three months following, standard androgen deprivation therapy with a 3-month depot injection of an LHRH agonist. Patients were men (n = 34) with prostate cancer who had not previously received androgen depriving therapy, and had PSA-recurrent and/or metastatic prostate cancer. In the second study, blood was collected immediately preceding and three months following initiation of treatment with a poxviral vaccine encoding PSA (PSA-TRICOM) []. Patients were men (n = 31) with castrate-resistant metastatic prostate cancer. In the third study, blood was collected immediately preceding, and at three months following, biweekly treatment with a DNA vaccine encoding prostatic acid phosphatase (PAP) []. Patients were men (n = 21) with non-castrate, PSA-recurrent prostate cancer without evidence of metastatic disease.

IgG responses to prostate-associated antigens are elicited following prostate cancer-directed therapies. Sera from patients pretreatment and three months following treatment with androgen deprivation ((a), n = 34), a PSA-targeted viral vaccine ((b), n = 31), or a PAP-targeted DNA vaccine ((c), n = 21) were evaluated for IgG responses to 126 prostate-associated antigens. Antigens (detailed in Supplemental table 1) are grouped according to the original studies from which they were derived (prostatitis antigens, cancer-testis antigens, or antigens detected by SEREX from individual subjects), and IgG responses were scored as previously described []. Shown is a heatmap representing gain of response pretreatment to posttreatment (light green), loss of response following treatment (black), or no change in response (dark green) for all subjects (in rows) and all antigens (in columns).

IgG responses to specific prostate-associated antigens are detectable several months after initiation of treatment with ADT or a PAP vaccine. Immunoblot analysis was performed with the same panel of antigens using sera from individual subjects for whom sera was available 12 months after beginning treatment with ADT (24 of the original 34) or the PAP vaccine (19 of the original 21). The heatmap similarly shows gain of response pretreatment to 12 months posttreatment (light green), loss of response following treatment (black), or no change in response (dark green) for all subjects (in rows) and all antigens (in columns).

Structure of Bayesian Belief Network representing selected subset of biomarkers. The structure of the network represents the hierarchy of conditional dependence between features, hence we can identify that the two first degree associates of clinical response are change in IgG responses to BACRP11-321G3 and chromosome 1 gene contig 1. Further, because IgG response to BAC RP11-321G3 is a shared child between PSA decline and IgG response to RP11-738B7 DNA on chromosome 7, IgG response to RP11-738B7 DNA on chromosome 7 still influences the estimate of PSA decline even when IgG response to BAC RP11-321G3 is known.